CN107311865A - Eugenol aliphatic ester derivatives and its application and preparation method - Google Patents

Abstract

Eugenol fatty acid ester analog derivative of the present invention and its application and preparation method.Eugenol fatty acid ester is as obtained from eugenol and straight chain fatty acid acid through esterification.Method is that aliphatic acid prepares acyl chlorides with thionyl chloride reaction first, and eugenol is mixed with the pyridine or triethylamine of equimolar amounts, is then added dropwise under ice cooling, 4 in the acyl chlorides prepared and reacts and generate eugenol fatty acid ester.Eugenol ester can be used for patch, cataplasm, ointment, gel, spray external preparation as transdermal enhancer, so as to improve the percutaneous absorbtion amount of medicine, be a kind of good percutaneous absorbtion transdermal enhancer, have broad application prospects.

Description

Eugenol fatty acid ester derivatives and their application and preparation method

technical field

The invention relates to a derivative and its application and preparation method, especially a eugenol fatty acid ester derivative and its application and preparation method.

Background technique

Transdermal drug delivery systems (TDDS) are a new class of preparations in which drugs are absorbed through the skin and enter the systemic circulation to produce curative effects. Once TDDS appeared, it attracted the attention of the medical community due to its long-lasting, constant and controllable blood drug concentration, avoiding the hepatic first-pass effect, convenient administration, and high patient compliance. The skin is a natural barrier that prevents the entry of foreign substances into the body and the loss of body water. The skin is composed of epidermis, dermis and subcutaneous tissue. The epidermis can be divided into stratum corneum and active epidermis. The stratum corneum is the main barrier for drug transdermal absorption. After transdermal administration of most drugs, the permeation rate is far below the therapeutic requirements. Therefore, in order to develop more drugs into TDDS, finding ways to increase drug permeation is a top priority in TDDS research. The chemical penetration enhancing method using a penetration enhancer is the oldest method, but it is the simplest, safe, cheap and practical method. Penetration enhancers are mostly derived from natural products (volatile oils), which have the advantages of strong permeability-enhancing activity, low toxicity, small irritation, and penetration-enhancing effects on both hydrophilic and lipophilic drugs. However, the volatility of most volatile oils will hinder the production and storage of percutaneous absorption preparations. Because it is volatile, it will cause unstable content in the formulation, and lead to poor reproducibility between batches. Commonly used terpenoid penetration enhancers such as l-menthol, α-terpineol, eugenol, etc., the applicant of l-menthol has carried out structural modification, prepared 17 kinds of derivatives, and screened out relatively L-menthol low toxicity, high efficiency, non-volatile penetration enhancer (Ligang Zhao, Liang Fang, Yongnan Xu, et al.Transdermaldelivery of penetrants with differing lipophilicities using O-acylmentholderivatives as penetration enhancers.Eur J Pharm Biopharm,2008,69 :199–213; Ligang Zhao, Liang Fang, Yongnan Xu, et al.Effect of O-acylmenthol ontransdermal delivery of drugs with different lipophilicity.Int J Pharm,2008,352:92–103), and applied for a patent (patent certificate No.: ZL200710158246.1). Eugenol is the main component of clove and clove basil oil. As a natural spice, it has pharmacological activities such as antipyretic, analgesic, anti-inflammatory, anti-oxidation, inhibition of arachidonic acid metabolism, anti-platelet aggregation, and anti-thrombosis. Commonly used in analgesia, anesthesia, anti-inflammatory and other aspects. Eugenol has an excellent transdermal absorption promotion effect, and can exert the dual effects of promoting penetration and treatment. Studies have shown that eugenol also has significant transdermal penetration-enhancing effects on various drugs such as catechin, sinomenine hydrochloride, and 5-fluorouracil (Chen Caide, Han Zaihong, Li Dongxia, Screening of penetration enhancers for compound catechin antidiarrheal film agent .Chinese Journal of Hospital Pharmacy, 2011, 31(14), 1159-1162; Han Tengfei, Cheng Liang, Wei Honghua, Preparation and properties of sinomenine hydrochloride ethotoplasts, Chinese Herbal Medicine, 2012, 43(7), 1300-1305; Shen Qi`, Cai Zhenzhen, Xu Lianying, Research on the role of cloves in promoting the transdermal absorption of 5-fluorine gills, Chinese herbal medicine, 1999, 30(8), 601-602), but its boiling point is low, volatile, The content in the preparation is not stable. The present inventors modified its structure, synthesized a series of fatty acid ester derivatives, and systematically studied its permeation-promoting activity.

Contents of the invention

The object of the present invention is to provide a eugenol fatty acid ester derivative with penetration-promoting activity and its application in transdermal preparations and its preparation method.

The present invention adopts following technical scheme:

A kind of eugenol fatty acid ester derivative, the general structural formula of this derivative is as follows:

The preferred scheme of eugenol fatty acid ester derivative is as follows:

Eugenol is natural or synthetic eugenol; fatty acids include saturated straight-chain fatty acids and unsaturated straight-chain fatty acids.

The saturated fatty acid is straight chain fatty acid of C ₂ ~C ₁₈ or R=C ₁ ~C ₁₇ , and the R of unsaturated fatty acid is: (CH ₂ ) ₇ CH=CH(CH ₂ ) ₇ CH ₃ .

The saturated fatty acid includes propionic acid, butyric acid, hexanoic acid, heptanoic acid, caprylic acid, capric acid, dodecanoic acid, tetradecanoic acid, hexadecanoic acid and octadecanoic acid; the unsaturated fatty acid is oleic acid.

The application of eugenol fatty acid ester derivative adopts following technical scheme:

It can be used as a percutaneous absorption and penetration enhancer to prepare transdermal drug preparations, improve the percutaneous absorption of drugs, and increase the cumulative penetration of drugs.

The application of eugenol fatty acid ester derivative adopts following preferred scheme:

The preparations for transdermal administration are external preparations of patch, cataplasm, latex, gel, cream, ointment, liniment or spray.

The preparation method of the preparation is as follows: the drug ingredients, the pressure-sensitive adhesive and the eugenol fatty acid ester derivative are fully mixed, and then coated on the anti-adhesive layer by transferring, dried at 30-100°C, and then coated with PVC or no The backing material of the spun cloth is compounded to obtain a transdermal drug delivery preparation.

The medicinal ingredient is selected from one of diclofenac potassium, indomethacin, ketoprofen, oxybutynin, flurbiprofen, bisoprolol, lidocaine, selegiline or isosorbide dinitrate.

The pressure-sensitive adhesive is one selected from silicone pressure-sensitive adhesives, acrylate pressure-sensitive adhesives or polyisobutylene pressure-sensitive adhesives.

The effective dosage of the eugenol fatty acid ester derivative is 0.5%-20% (w/w).

The optimum dosage of eugenol fatty acid ester derivative is 3%-10% (w/w).

After adding diclofenac potassium to the pressure-sensitive adhesive, stir until the drug is completely dissolved in the pressure-sensitive adhesive solution; after that, add eugenol fatty acid ester derivatives, glycerin, ethyl acetate and hydroxypropyl cellulose, and continue stirring until a clear Viscous homogeneous solution; then, transfer coating on the anti-adhesive layer with an experimental coating machine, after drying at 30°C to 100°C, compound the backing with non-woven fabric to obtain diclofenac potassium patch.

The preparation method of eugenol fatty acid ester derivative adopts following technical scheme:

Eugenol fatty acid ester derivatives are obtained by reacting with eugenol after preparing fatty acid chlorides.

The preferred scheme of preparation method is:

Eugenol fatty acid ester derivatives were reacted with thionyl chloride to prepare fatty acid chlorides.

Fatty acyl chloride reacts with eugenol, and the solvent used in the preparation process is a low-toxic organic solvent that removes water.

Collect fatty acids with different chemical structures, and synthesize eugenol ester derivatives according to the synthetic route shown below; Compounds 1-11 are all synthesized by the following route:

The above-mentioned 11 kinds of eugenol derivatives synthesized by the present invention can be used as percutaneous absorption and penetration enhancers to prepare transdermal drug preparations (patches, cataplasms, emulsions, creams, gels, ointments, paints, etc.) medicaments, sprays, etc.), and the low volatility of the derivatives can also be used as a eugenol substitute in external preparations containing eugenol.

The compound described in the invention can be applied in transdermal drug delivery preparations to enhance the penetration ability of medicines, and can also be used as spices to cover the bad smell of the preparations, thus having wide potential application prospects. The preparation method is suitable for industrial production, safe and easy to store.

Description of drawings

Figure 1 is a diagram of cumulative penetration of eugenol fatty acid esters in patches to promote transdermal absorption of diclofenac potassium.

Fig. 2 is a diagram of cumulative penetration of eugenol fatty acid esters applied in patches to promote transdermal absorption of indomethacin.

Figure 3 is a diagram of cumulative penetration of eugenol fatty acid esters applied in patches to promote transdermal absorption of ketoprofen.

Fig. 4 is a diagram of the cumulative penetration amount of eugenol fatty acid ester applied in the patch to promote the transdermal absorption of oxybutynin.

Fig. 5 is a diagram of cumulative penetration of eugenol fatty acid esters applied in patches to promote transdermal absorption of influrbiprofen.

Fig. 6 is a diagram of cumulative penetration of eugenol fatty acid esters applied in patches to promote transdermal absorption of bisoprolol.

Fig. 7 is a diagram of cumulative permeation amount of eugenol fatty acid ester applied in patch to promote transdermal absorption of lidocaine.

Fig. 8 is a diagram of cumulative penetration of eugenol fatty acid esters applied in patches to promote transdermal absorption of selegiline.

Fig. 9 is a diagram of cumulative penetration amount of eugenol fatty acid ester applied in patch to promote transdermal absorption of isosorbide dinitrate.

detailed description

Below in conjunction with accompanying drawing and embodiment the present invention is described in further detail:

Example 1:

Take 14.8g (0.2mol) of propionic acid, add 17.85g (0.15mol) of thionyl chloride, mix well, react at 60°C for 3 hours, and let cool (0°C). Add 20 ml of eugenol-pyridine solution containing 16.4 g (0.1 mol), continue to react under ice bath for 3 hours, adjust the reaction solution to pH 6-7 with NaOH solution, separate the organic layer, extract the aqueous layer with ethyl acetate, The organic layers were combined, washed with saturated brine, dried overnight with anhydrous Na ₂ SO ₄ , the solvent was evaporated, column chromatography (silica gel 200-300 mesh), ethyl petroleum ether and ethyl acetate (volume ratio 15:1) were washed The solvent was removed, and the eluent was evaporated to obtain 19.64 g of a colorless liquid with a yield of 91%. The ¹ HNMR and MS data of the product are as follows: ESI-MS m/z: 219.3[M+1] ⁺ ; ¹ H-NMR (200MHz) δ: 6.83 (1H, d, J=8.8Hz, 5′-H), 6.66(1H,dd,J=8.4,1.8Hz,6'-H),6.65(1H,d,J=1.8Hz,2'-H),5.94(1H,m,2-H),5.05(2H ,m,1-H),3.86(3H,s,OCH ₃ ),3.30(2H,dt,J=6.6,1.5Hz,3-H),2.2-1.72(m,2H),1.68(s,3H ).

Example 2:

Take 17.6g (0.2mol) of butyric acid, add 17.85g (0.15mol) of thionyl chloride, mix well, react at 60°C for 3 hours, and let cool. Add 20 ml of eugenol-pyridine solution containing 16.4 g (0.1 mol), continue to react under ice bath for 3 hours, adjust the reaction solution to pH 6-7 with NaOH solution, separate the organic layer, extract the aqueous layer with ethyl acetate, The organic layers were combined, washed with saturated brine, dried overnight with anhydrous Na ₂ SO ₄ , evaporated to remove the solvent, and subjected to column chromatography (silica gel 200-300 mesh), ethyl petroleum ether and ethyl acetate (15:1) as eluents , evaporated to remove the eluent to obtain 21.91 g of colorless liquid, yield: 91.4%. The ¹ HNMR and MS data of the product are as follows: ESI-MS m/z: 233.3[M+1] ⁺ ; ¹ H-NMR (200MHz) δ: 6.83 (1H, d, J=8.8Hz, 5′-H), 6.66(1H,dd,J=8.4,1.8Hz,6'-H),6.65(1H,d,J=1.8Hz,2'-H),5.94(1H,m,2-H),5.05(2H ,m,1-H),3.86(3H,s,OCH ₃ ),3.30(2H,dt,J＝6.6,1.5Hz,3-H),2.2-1.72(m,4H),1.68(s,3H ).

Example 3:

Take 23.2g (0.2mol) of hexanoic acid, add 17.85g (0.15mol) of thionyl chloride, mix well, react at 60°C for 3 hours, and let cool. Add 20 ml of eugenol-pyridine solution containing 16.4 g (0.1 mol), continue to react under ice bath for 3 hours, adjust the reaction solution to pH 6-7 with NaOH solution, separate the organic layer, extract the aqueous layer with ethyl acetate, The organic layers were combined, washed with saturated brine, dried overnight with anhydrous Na ₂ SO ₄ , evaporated to remove the solvent, and subjected to column chromatography (silica gel 200-300 mesh), ethyl petroleum ether and ethyl acetate (15:1) as eluents , evaporated to remove the eluent to obtain 22.77 g of colorless liquid, yield: 91.4%. The ¹ HNMR and MS data of the product are as follows: ESI-MS m/z: 261.4[M+1] ⁺ ; ¹ H-NMR (200MHz) δ: 6.83 (1H, d, J=8.8Hz, 5′-H), 6.66(1H,dd,J=8.4,1.8Hz,6'-H),6.65(1H,d,J=1.8Hz,2'-H),5.94(1H,m,2-H),5.05(2H ,m,1-H),3.86(3H,s,OCH ₃ ),3.30(2H,dt,J＝6.6,1.5Hz,3-H),2.2-1.72(m,8H),1.68(s,3H ).

Example 4:

Take 26g (0.2mol) of heptanoic acid, add 17.85g (0.15mol) of thionyl chloride, mix well, react at 60°C for 3 hours, and let cool. Add 20 ml of eugenol-pyridine solution containing 16.4 g (0.1 mol), continue to react under ice bath for 3 hours, adjust the reaction solution to pH 6-7 with NaOH solution, separate the organic layer, extract the aqueous layer with ethyl acetate, The organic layers were combined, washed with saturated brine, dried overnight with anhydrous Na ₂ SO ₄ , evaporated to remove the solvent, and subjected to column chromatography (silica gel 200-300 mesh), ethyl petroleum ether and ethyl acetate (15:1) as eluents , evaporated to remove the eluent to obtain 26.41 g of colorless liquid, yield: 91%. The ¹ HNMR and MS data of the product are as follows: ESI-MS m/z: 275.4[M+1] ⁺ ; ¹ H-NMR (200MHz) δ: 6.83 (1H, d, J=8.8Hz, 5′-H), 6.66(1H,dd,J=8.4,1.8Hz,6'-H),6.65(1H,d,J=1.8Hz,2'-H),5.94(1H,m,2-H),5.05(2H ,m,1-H),3.86(3H,s,OCH ₃ ),3.30(2H,dt,J=6.6,1.5Hz,3-H),2.2-1.72(m,10H),1.68(s,3H ).

Example 5:

Take 28.8g (0.2mol) of octanoic acid, add 17.85g (0.15mol) of thionyl chloride, mix well, react at 60°C for 3 hours, and let cool. Add 20 ml of eugenol-pyridine solution containing 16.4 g (0.1 mol), continue to react under ice bath for 3 hours, adjust the reaction solution to pH 6-7 with NaOH solution, separate the organic layer, extract the aqueous layer with ethyl acetate, The organic layers were combined, washed with saturated brine, dried overnight with anhydrous Na ₂ SO ₄ , evaporated to remove the solvent, and subjected to column chromatography (silica gel 200-300 mesh), ethyl petroleum ether and ethyl acetate (15:1) as eluents , evaporated to remove the eluent to obtain 25.4 g of colorless liquid, yield: 86%. The ¹ HNMR and MS data of the product are as follows: ESI-MS m/z: 289.4[M+1] ⁺ ; ¹ H-NMR (200MHz) δ: 6.83 (1H, d, J=8.8Hz, 5′-H), 6.66(1H,dd,J=8.4,1.8Hz,6'-H),6.65(1H,d,J=1.8Hz,2'-H),5.94(1H,m,2-H),5.05(2H ,m,1-H),3.86(3H,s,OCH ₃ ),3.30(2H,dt,J＝6.6,1.5Hz,3-H),2.2-1.72(m,12H),1.68(s,3H ).

Embodiment 6:

Take 34.4g (0.2mol) of capric acid, add 17.85g (0.15mol) of thionyl chloride, mix well, react at 60°C for 3 hours, and let cool. Add 20 ml of eugenol-pyridine solution containing 16.4 g (0.1 mol), continue to react under ice bath for 3 hours, adjust the reaction solution to pH 6-7 with NaOH solution, separate the organic layer, extract the aqueous layer with ethyl acetate, The organic layers were combined, washed with saturated brine, dried overnight with anhydrous Na ₂ SO ₄ , evaporated to remove the solvent, and subjected to column chromatography (silica gel 200-300 mesh), ethyl petroleum ether and ethyl acetate (15:1) as eluents , evaporated to remove the eluent to obtain 32.83 g of colorless liquid, yield: 93.5%. The ¹ HNMR and MS data of the product are as follows: ESI-MS m/z: 317.5[M+1] ⁺ ; ¹ H-NMR (200MHz) δ: 6.83 (1H, d, J=8.8Hz, 5′-H), 6.66(1H,dd,J=8.4,1.8Hz,6'-H),6.65(1H,d,J=1.8Hz,2'-H),5.94(1H,m,2-H),5.05(2H ,m,1-H),3.86(3H,s,OCH ₃ ),3.30(2H,dt,J＝6.6,1.5Hz,3-H),2.2-1.72(m,16H),1.68(s,3H ).

Embodiment 7:

Take 40 g (0.2 mol) of dodecanoic acid, add 17.85 g (0.15 mol) of thionyl chloride, mix well, react at 60°C for 3 hours, and let cool. Add 20 ml of eugenol-pyridine solution containing 16.4 g (0.1 mol), continue to react under ice bath for 3 hours, adjust the reaction solution to pH 6-7 with NaOH solution, separate the organic layer, extract the aqueous layer with ethyl acetate, The organic layers were combined, washed with saturated brine, dried overnight with anhydrous Na ₂ SO ₄ , evaporated to remove the solvent, and subjected to column chromatography (silica gel 200-300 mesh), ethyl petroleum ether and ethyl acetate (15:1) as eluents , evaporated to remove the eluent to obtain 33.62 g of colorless liquid, yield: 90.5%. The ¹ HNMR and MS data of the product are as follows: ESI-MS m/z: 345.5[M+1] ⁺ ; ¹ H-NMR (200MHz) δ: 6.83 (1H, d, J=8.8Hz, 5′-H), 6.66(1H,dd,J=8.4,1.8Hz,6'-H),6.65(1H,d,J=1.8Hz,2'-H),5.94(1H,m,2-H),5.05(2H ,m,1-H),3.86(3H,s,OCH ₃ ),3.30(2H,dt,J＝6.6,1.5Hz,3-H),2.2-1.72(m,20H),1.68(s,3H ).

Embodiment 8:

Take 45.6g (0.2mol) of myristic acid, add 17.85g (0.15mol) of thionyl chloride, mix well, react at 60°C for 3 hours, and let cool. Add 20 ml of eugenol-pyridine solution containing 16.4 g (0.1 mol), continue to react under ice bath for 3 hours, adjust the reaction solution to pH 6-7 with NaOH solution, separate the organic layer, extract the aqueous layer with ethyl acetate, The organic layers were combined, washed with saturated brine, dried overnight with anhydrous Na ₂ SO ₄ , evaporated to remove the solvent, and subjected to column chromatography (silica gel 200-300 mesh), ethyl petroleum ether and ethyl acetate (15:1) as eluents , distilled off the eluent to obtain 34.6 g of colorless liquid, yield: 89%. The ¹ HNMR and MS data of the product are as follows: ESI-MS m/z: 373.5[M+1] ⁺ , 1H-NMR (200MHz) δ: 6.83 (1H, d, J = 8.8Hz, 5′-H), 6.66 (1H,dd,J=8.4,1.8Hz,6'-H),6.65(1H,d,J=1.8Hz,2'-H),5.94(1H,m,2-H),5.05(2H, m,1-H),3.86(3H,s,OCH ₃ ),3.30(2H,dt,J＝6.6,1.5Hz,3-H),2.2-1.72(m,24H),1.68(s,3H) .

Embodiment 9:

Take 51.2g (0.2mol) of palmitic acid, add 17.85g (0.15mol) of thionyl chloride, mix well, react at 60°C for 3 hours, and let cool. Add 20 ml of eugenol-pyridine solution containing 16.4 g (0.1 mol), continue to react under ice bath for 3 hours, adjust the reaction solution to pH 6-7 with NaOH solution, separate the organic layer, extract the aqueous layer with ethyl acetate, The organic layers were combined, washed with saturated brine, dried overnight with anhydrous Na ₂ SO ₄ , evaporated to remove the solvent, and subjected to column chromatography (silica gel 200-300 mesh), ethyl petroleum ether and ethyl acetate (15:1) as eluents , evaporated to remove the eluent, to obtain a white solid 36.3g, yield: 87%. The ¹ HNMR and MS data of the product are as follows: ESI-MS m/z: 401.6[M+1] ⁺ , ¹ H-NMR (200MHz) δ: 6.83 (1H, d, J=8.8Hz, 5′-H), 6.66(1H,dd,J=8.4,1.8Hz,6'-H),6.65(1H,d,J=1.8Hz,2'-H),5.94(1H,m,2-H),5.05(2H ,m,1-H),3.86(3H,s,OCH ₃ ),3.30(2H,dt,J=6.6,1.5Hz,3-H),2.2-1.72(m,28H),1.68(s,3H ).

Example 10:

Take 56.8g (0.2mol) of octadecanoic acid, add 17.85g (0.15mol) of thionyl chloride, mix well, react at 60°C for 3 hours, and let cool. Add 20 ml of eugenol-pyridine solution containing 16.4 g (0.1 mol), continue to react under ice bath for 3 hours, adjust the reaction solution to pH 6-7 with NaOH solution, separate the organic layer, extract the aqueous layer with ethyl acetate, The organic layers were combined, washed with saturated brine, dried overnight with anhydrous Na ₂ SO ₄ , evaporated to remove the solvent, and subjected to column chromatography (silica gel 200-300 mesh), ethyl petroleum ether and ethyl acetate (15:1) as eluents , evaporated to remove the eluent to obtain 35.9 g of white solid, yield: 85%. The ¹ HNMR and MS data of the product are as follows: ESI-MS m/z: 399.6[M+1] ⁺ ; ¹ H-NMR (200MHz) δ: 6.83 (1H, d, J=8.8Hz, 5′-H), 6.66(1H,dd,J=8.4,1.8Hz,6'-H),6.65(1H,d,J=1.8Hz,2'-H),5.94(1H,m,2-H),5.05(2H ,m,1-H),3.86(3H,s,OCH ₃ ),3.30(2H,dt,J＝6.6,1.5Hz,3-H),2.2-1.72(m,232H),1.68(s,3H ).

Example 11:

Take 56.4g (0.2mol) of oleic acid, add 17.85g (0.15mol) of thionyl chloride, mix well, react at 60°C for 3 hours, and let cool. Add 20 ml of eugenol-pyridine solution containing 16.4 g (0.1 mol), continue to react under ice bath for 3 hours, adjust the reaction solution to pH 6-7 with NaOH solution, separate the organic layer, extract the aqueous layer with ethyl acetate, The organic layers were combined, washed with saturated brine, dried overnight with anhydrous Na ₂ SO ₄ , evaporated to remove the solvent, and subjected to column chromatography (silica gel 200-300 mesh), ethyl petroleum ether and ethyl acetate (15:1) as eluents , evaporated to remove the eluent to obtain 38.14 g of slightly yellow liquid, yield: 84%. The ¹ HNMR and MS data of the product are as follows: ESI-MS m/z: 397.6[M+1] ⁺ ; ¹ H-NMR (200MHz) δ: 6.83 (1H, d, J=8.8Hz, 5′-H), 6.66(1H,dd,J=8.4,1.8Hz,6'-H),6.65(1H,d,J=1.8Hz,2'-H),5.94(1H,m,2-H),5.05(2H ,m,1-H),3.86(3H,s,OCH ₃ ),3.30(2H,dt,J=6.6,1.5Hz,3-H),2.38(2H,t,J=7.4Hz),2.2- 1.74(m,28H),1.68(s,3H).

Example 12: Eugenol Derivatives Promote Transdermal Absorption of Diclofenac Potassium in Patches

Preparation of skin: Take male rats with a body weight of 180g-220g, inject 1ml of urethane solution with a mass ratio of 25% into the abdominal cavity for anesthesia, cut off the abdominal hair, and kill them. Rinse with saline for 3 times, store in -20°C refrigerator for short term (use within 7 days), and set aside.

Preparation of patch: In a 30ml sample bottle, filled with acrylate pressure sensitive adhesive. After adding diclofenac potassium, stir at 300 rpm until the drug ingredients are completely dissolved in the pressure-sensitive adhesive solution. Then add the absorption penetration enhancer and other ingredients (as shown in Table 1), and continue to stir until a uniform solution is formed. Subsequently, it was transferred and coated on the anti-adhesive layer with an experimental coater, dried at 30°C to 100°C, compounded with a backing non-woven fabric, and punched into a size of ⁷ ×7cm2 to obtain a diclofenac potassium patch.

Table 1

METHODS: The transdermal absorption test used a horizontal double-chamber diffusion cell. The prepared diclofenac potassium patch was applied to the treated skin stratum corneum. The pH 7.4 phosphate buffer solution was used as the receiving solution, and the absorption was determined by HPLC. Calculate the amount of drug in the pool, and calculate the cumulative permeation volume and permeation flux. Wherein the concentration of the penetration enhancer in the diclofenac potassium patch is (0 or 5% eugenol or equimolar concentration with 5% eugenol).

Example 13:

The same method as in Example 12 was used except that indomethacin was used instead of diclofenac potassium.

Table 2

Example 14:

Except replacing diclofenac potassium with ketoprofen, use the same method with embodiment 12.

table 3

Example 15:

Except that oxybutynin was used instead of diclofenac potassium, the same method as in Example 12 was used.

Table 4

Example 16:

Except that flurbiprofen was used instead of diclofenac potassium, the same method as in Example 12 was used.

table 5

Example 17:

Except replacing diclofenac potassium with bisoprolol, use the same method with embodiment 12.

Table 6

Example 18:

Except replacing diclofenac potassium with lidocaine, use the same method with embodiment 12.

Table 7

Example 19:

Except using selegiline instead of diclofenac potassium, the same method as in Example 12 was used.

Table 8

Example 20:

The same method as in Example 12 was used except that diclofenac potassium was replaced with isosorbide dinitrate.

Table 9

Claims (16)

1. a kind of eugenol aliphatic ester derivatives, the general structure of the derivative is as follows：

2. eugenol aliphatic ester derivatives according to claim 1, it is characterised in that：Eugenol is natural or synthetic fourth Fragrant phenol；Aliphatic acid includes saturated straight chain aliphatic acid and unsaturated straight chain fatty acid.

3. eugenol aliphatic ester derivatives according to claim 2, it is characterised in that：Saturated fatty acid is C₂~C₁₈'s Straight chain fatty acid or R=C₁~C₁₇, the R of unrighted acid is：(CH₂)₇CH=CH (CH₂)₇CH₃。

4. eugenol aliphatic ester derivatives according to claim 3, it is characterised in that：Described saturated fatty acid includes Propionic acid, butyric acid, caproic acid, enanthic acid, octanoic acid, capric acid, lauric acid/dodecanoic acid, tetradecylic acid, hexadecylic acid and stearic acid；Described unrighted acid For oleic acid.

5. a kind of application of eugenol aliphatic ester derivatives as described in any one in Claims 1-4, its feature exists In：As percutaneous absorbtion transdermal enhancer application, percutaneous drug administration preparation is prepared, the percutaneous absorbtion of medicine is improved, increases the accumulation of medicine Transit dose.

6. the application of eugenol aliphatic ester derivatives according to claim 5, it is characterised in that：Percutaneous drug administration preparation point It is not patch, cataplasm, emulsion agent, gel, cream, ointment, liniment or spray class external preparation.

7. the application of eugenol aliphatic ester derivatives according to claim 5, it is characterised in that：The preparation method of preparation It is as follows：After drug ingedient, pressure sensitive adhesive and eugenol aliphatic ester derivatives are sufficiently mixed with metastatic coating be made in it is anti-sticking On layer, by 30~100 DEG C of dryings, then with the Material cladding of mounting of PVC or non-woven fabrics is included, that is, percutaneous dosing system is obtained Agent.

8. the application of eugenol aliphatic ester derivatives according to claim 7, it is characterised in that：Drug ingedient is selected from double The fragrant sour potassium of chlorine, Indomethacin, Ketoprofen, oxybutynin, Flurbiprofen, bisoprolol, lidocaine, selegiline or nitric acid are different One kind in sorb ester.

9. the application of eugenol aliphatic ester derivatives according to claim 7, it is characterised in that：Pressure sensitive adhesive is to be selected from silicon One kind in ketone pressure sensitive adhesive, acrylate pressure-sensitive adhesive or Medical PSA.

10. the application of eugenol aliphatic ester derivatives according to claim 5, it is characterised in that：Eugenol aliphatic acid The effective dose of ester derivant is 0.5%-20% (w/w).

11. the application of eugenol aliphatic ester derivatives according to claim 5, it is characterised in that：Eugenol aliphatic acid The optimum amount of ester derivant is 3%-10% (w/w).

12. the application of eugenol aliphatic ester derivatives according to claim 5, it is characterised in that：It will add in pressure sensitive adhesive Enter after Diclofenac Potassium, stirring is until medicine is completely dissolved in pressure-sensitive sol solution；Afterwards, add eugenol aliphatic ester derivatives and Glycerine, ethyl acetate and hydroxypropyl cellulose, continue to stir, until forming the sticky shape homogeneous solution of clarification；Then, using experiment With coating machine transfer coated on adherent layer, after 30 DEG C~100 DEG C dryings, combination backing non-woven fabrics produces Diclofenac Potassium Patch.

13. a kind of preparation method of eugenol aliphatic ester derivatives, it is characterised in that：Eugenol aliphatic ester derivatives pass through Prepare after fat acyl chloride and to be reacted with eugenol.

14. the preparation method of eugenol aliphatic ester derivatives according to claim 13, it is characterised in that：Eugenol fat Fat acid ester derivant with thionyl chloride reaction by preparing fat acyl chloride.

15. the preparation method of eugenol aliphatic ester derivatives according to claim 13, it is characterised in that：Fat acyl chloride Reacted with eugenol, solvent for use is the low toxicity organic solvent for removing water in preparation process.

16. the preparation method of eugenol aliphatic ester derivatives according to claim 13, it is characterised in that：Collect different The aliphatic acid of chemical constitution, according to synthetic route as follows, synthesizes eugenol ester analog derivative；Compound 1-11, is adopted Synthesized as follows with route：